12, 17-dioxygenated steroids



United States Patent 12,17-DIOXYGENATED STEROIDS Philip E. Shaw,Bethlehem, N.Y., assignor to Sterling Drug Inc., New York, N.Y., acorporation of Delaware No Drawing. Filed July 13, 1965, Ser. No.471,735 20 Claims. (Cl. 260-23955) ABSTRACT OF THE DISCLOSURE Theaddition of Grignard reagents, R-Mg-halide, to;3-androstane-3u,12a-diol-17-one provides the unexpected17a-hydroxy-17-R-isomers. The latter are converted to 3-oxo and 3-oxo-Acompounds, and to their 12,17-cyclic ketonide derivatives. Novelderivatives of 5/3-androstane-3a,12a,17,3-triol are also described. Thecompounds of the invention'modify serum electrolyte content, enhancedesoxycorticosterone acetate activity, reverse urinary nitrogen loss,and possess progestational activity.

wherein R is lower-alkyl, lower-alkenyl or lower-alkynyl; and R ishydrogen or carboxylic acyl having up to (and thus including) twelvecarbon atoms.

When R in the above Formula I is lower-alkyl it stands for an alkylgroup having from one to six carbon atoms, thus including methyl, ethyl,propyl, isopropyl, butyl, hexyl, and the like.

When R in the above'Formula I is lower-alkenyl or lower-alkynyL itstands for an alkenyl or alkynyl group, preferably having from two tosix carbon atoms, thus including such groups as allyl, Z-buten-l-yl,ethynyl, 2- propyn-l-yl, 3-hexen-1-yl, 2-hexyn-1-yl, and the like.

The compounds of Formula I wherein R is carboxylic acyl having up totwelve carbon atoms are prepared from the 3a,12a-dihydroxy compounds byconventional esterification reactions.

The term lower-carboxylic acyl having up to (and therefore including)twelve carbon atoms refers to acyl radicals derived from carboxylicacids having up to (and therefore including) twelve carbon atoms and amolecular weight less than about 250. Representative of thelower-carboxylic acyl radicals which can be present are lower-alkanoyl,e.g., acetyl, propionyl, isobutyryl, caproyl, heptanoyl, octanoyl,dodecanoyl, trimethylacetyl, and the like; cycloalkyl-lower-alkanoylwherein cycloalkyl has ice 5-6 ring members, e.g.,B-cyclopentylpropionyl, B-cyclohexylpropionyl, and the like; benzoyl;phenyl-loweralkanoyl or -alkenoyl, e.g., phenylacetyl,fl-phenylpropionyl, cinnamoyl, and the like; phenoxy-lower-alkanoyl,e.g., p-chlorophenoxyacetyl; and pyridylcarbonyl, e.g., nicotinoyl andisonicotinoyl. In acyl radicals containing a phenyl group, the benzenering thereof can be unsubstituted or substituted by any number and kindof substituents inert under the reaction conditions used, includinglower-alkyl, for example p-tolyl; lower-alkoxy, for example3,4-dimethoxyphenyl; halogen (including fluorine, chlorine, bromine andiodine), for example 2-bromophenyl; and nitro, for examplep-nitrophenyl. The loweralkyl and lower-alkoxy groups can have from oneto four carbon atoms.

Compounds of Formula I wherein R is lower-alkyl of two or more carbonatoms can be alternatively produced by catalytic hydrogenation of thecorresponding compounds wherein R is lower-alkenyl or lower-alkynyl.Partial'hydrogenation of compounds wherein R is loweralkynyl affords thecorresponding compounds wherein R is lower-alkenyl.

The compounds of Formula I and their isomers having the17a-R-l7fl-hydroxy configuration are readily converted by oxidation anddehydrogenation reactions to further compounds of the invention havingthe formulas and III

wherein R is lower-alkyl, lower-alkenyl or lower-alkynyl; and Z isCHM-OH), CH(u-OAcyl) or @O, Acyl being carboxylic acyl having up totwelve carbon atoms. The various terms have the same meanings as givenhereinabove.

The 3-oxo group in compounds of Formula II is formed by oxidation of thecorresponding 3-hydroxy compounds, as with chromic oxide orN-bromoacetamide. The 3-oxo- A structure of compounds of Formula III isproduced from compounds of Formula II by bromination at C-4 anddehydrobromination with an organic base or with lithium halide andlithium carbonate.

The configuration at C-17 in the Grignard products derived from5B-androstane-3a,12u-diol-l7-one was determined by preparation of thecorresponding 30:,12a-diacetates of each epimer followed by hydrolysisof each diacetate in aqueous methanolic potassium hydroxide at refluxtemperature for 30 minutes. The 17a-R derivative was only partiallyhydrolyzed to the l2a-monoacetate whereas the 17fi-R derivative wascompletely hydrolyzed to the 3a,12u,17u-triol. The 17a-hydroxyl groupbears a 1,3-diaxia1 relationship to the 12u-substituent and thus canassist in its hydrolysis.

Further evidence of the configurations assigned to the 17-substituentsin the Grignard products was obtained by treating each isomer underacetonide formation conditions, for example with acetone containing atrace of a strong acid such as perchloric acid. Only one isomer formedan acetonide. This isomer must be the 17;.3-R- 17a-hydroxy isomer,because examination of molecular models revealed that the stericarrangement of the 12 xand 17fi-hydroxy groups would prohibit acetonideformation. Such ketal formation leads to another aspect of the inventionwhich relates to compounds having the formulas and where X is CHM-OH),CH(a-OAcyl) or C O, Acyl being carboxylic acyl having up to twelvecarbon atoms; R is lower-alkyl, lower-alkenyl or lower-alkynyl; and R"and R are lower-alkyl. The groups defining R have the same meaningsgiven hereinabove; and the lower-alkyl groups R" and R can have from oneto six carbon atoms.

The compounds of Formulas IV and V are prepared from compounds ofFormula I and from compounds of Formulas II and III having thel7fi-R-l7a-hydroxy configuration by reacting them with lower-aliphaticketones, R"COR', in the presence of a strong acid, e.g., perchloricacid, p-toluenesulfonic acid, sulfosalicylic acid, hydrochloric acid orthe like.

A further aspect of the invention resides in ketal derivatives in thepregnane series having the formula wherein X, R" and R' have the samemeanings given hereinabove in connection with Formulas IV and V.

The compounds of Formula VI are prepared as follows from the known3a,12a-dihydroxy-Sfl-pregnan-ZO- one. The latter when treated withoxygen is tertiary-butyl alcohol containing potassium tertiary-butoxideis conand VII

VIII

wherein X is CHM-OH), CH(a-OAcyl) or C O; Z is CH(;3-OH), CH(,B-OAcyl)or C=O; and R" and R' are lower-alkyl; Acyl in each instance beingcarboxylic acyl having up to (and thus including) twelve carbon atoms.The lower-alkyl group R" and R can have from one to six carbon atoms.

The compounds of Formulas VII and VIII can be prepared frornSB-androstane-Sa,12a,17;8-triol. The latter compound does not form a12,17-ketal with a ketone, RCOR"', because of the fl-configuration ofthe 17-hydroxy group. However, it has surprisingly been found that saidcompound does react with a ketone R"COR"' in the presence of a strongacid catalyst, for example, perchloric acid or boron trifiuoride, togive a compound of the formula The reaction takes place readily at roomtemperature.

The compounds of Formula IX are within the scope of Formula VII where Xis CHM-OH) and Z is C=O, and the former are readily converted to theremaining compounds within the scope of Formula VI by conventionaloxidation, reduction and esterification reactions, operating upon the 3-and/or 17-positions. The compounds of Formula VIII are prepared from thecompounds of Formula VII where X is C=O by bromination in the4-position, followed by dehydrobromination with an organic base or withlithium salts to form the 4,5- double bond.

Still another aspect of the invention is concerned with compounds of theformula wherein R" is hydrogen or carboxylic acyl having up to twelvecarbon atoms; and Z is CH(a-OH), CH(a- OAcyl) or 0 0, Acyl beingcarboxylic acyl having up to (and thus including) twelve carbon atoms.

The compounds of Formula VIII wherein Z is C==O when treated with astrong acid are converted to 4-androstene-l2a,17/3-diol-3-one [X, R" isH, Z is CH(tx-OH)]. Any strong acid, for example, hydrochloric,sulfuric, perchloric, p-toluenesulfonic, sulfosalicylic ortrifluoroacetic acids, can be employed, and the reaction takes place atroom temperature. In the event that trifluoroacetic acid is used,esterification of the l7-hydroxy group takes place, and17/3-trifluoroacetoxy-4-androsten-l2tz-ol-3-one [X, R"" is COCF Z isCH(oz-OH)] is produced. Other compounds within the scope of Formula Xare prepared by conventional oxidation and/or esterification reactionsand illustrated in the examples below.

Endocrinological evaluation of compounds of Formulas I, II, III, IV, Vand VI has demonstrated that they possess useful hormonal properties,for example, modification of serum electrolyte content, enhancement ofdesoxycorticosterone acetate activity, reversal of urinary nitrogenloss, and progestational activity. Efiective dose levels are from 10 tomg./ kg. and they can be formulated and administered to animal organismsin the same manner as other steroidal hormones.

The compounds of Formulas VII, VIII and X are useful as intermediates inpreparing known steroids, in-

eluding ll-dehydrotestosterone and derivatives and analogs thereof,known to be useful as anabolic and androgenic agents [Meystre et al.,Helv. Chim. Acta 32, 1978 (1949)]. For example, 17B-trifluoroacetoxy-4-androsten-12aol-3-one [X, R"" is COCF Z is CI-I(a- OH)] (prepared fromcompounds of Formula VIII, in turn prepared from compounds of FormulaVII) can be reacted with p-toluenesulfonyl chloride in pyridine to givethe 12u-p-toluenesulfonate, and the latter heated with potassiumtertiary-butoxide in dimethyl sulfoxide solution to affordll-dehydrotestosterone.

The following examples will further illustrate the invention without thelatter being limited thereby (melting points are corrected unlessotherwise stated. Except as noted, specific rotations wree measured inchloroform (1% solution) at 25 C. and ultraviolet spectra in 95%ethanol).

EXAMPLE 1 Grignard reaction of methylmagnesium bromide with3a,lZa-dihYdIOXY-SB-ll'ldIOStfiIl-17-0116 A solution of 10.36 g.(34.1'mmoles) of 3u,l2u-dihydroxy-Sfl-androstan-l7-one in 500 m1. oftetrahydrofuran was stirred magnetically as 400 ml. of a 3 Mmethylmagnesium bromide solution in ether was added dropwise in 30minutes. The resulting solution was refluxed for 36 hours and thencooled to room temperature. The complex was decomposed by adding 400 ml.of saturated ammonium chloride solution. More ether and water were addedand the layers were separate. The aqueous layer was extracted with twoportions of ether and the combined organic layer was washed withsaturated salt solution and dried over powdered magnesium sulfate, thenconcentrated to dryness. The residue was recrystallized from acetone togive 4.5 g. of material having M.P. 217-222 C. Concentration of themother liquor afforded 7.1 g. of a viscous brown oil. The crystallineportion of the product upon two further recrystallizations frorn'acetoneafforded 2.25 g. of l7a-methyl-5fl-androistane 3a,12ot,17)3 triol, M.P.224-228 C. Concentration of the combined mother liquor from the last tworecrystallizations afforded an additional 1.27 g., M.P. 220-224 C. (32%yield for the two crops). One recrystallization of the first crop fromethyl acetate afforded a sample with M.P. 225-228 C., [oc] +482 (1% inethanol).

The 7.1 g. of brown oil was recycled by dissolving it in 350 ml. oftetrahydrofuran and refluxing for 72 hours with 275 ml. ofmethylmagnesium bromide solution following the above procedure. Theproduct was an oil which was combined with the residue from the motherliquor of the second crop of 17u-methyl-5fi-androstane-3a,12a,17B-triol, and the resulting 7.6 g. of residue was acetylated withacetic anhydride and pyridine at room temperature. The product (about 10g. of oil) was taken up in 30% ether-70% pentane and chromatographed on300 g. of silica gel. Elution with 50% ether-50% pentane and 80%ether-20% pentane solvent mixtures afforded crystalline material whichwas combined and recrystallized from acetone-hexane to give 2.0 g. of17a-methyl-5fi-androstane- 3a,12a,17fl-Ui0l 3,12-diacetate, M.P. 166-168C. One recrystallization from acetone-hexane afforded a sample with M.P.166-168 C., [a] +101.2.

Early chromatograph fractions eluted with 50% ether- 50% pentane whichwere non-crystalline were combined with the residue obtained uponconcentration of the mother liquor from the crystallization of the abovediacetate,vand the resulting 5.5 g. of oil was hydrolyzed by refluxingit for 30 minutes with 4.4 g. of potassium hydroxide and 11 ml. of waterin 225 ml. of methanol. The reaction mixture was treated with 5 ml. ofacetic acid and the bulk of the methanol was removed by warming invacuo. Ether (500 ml.) was added followed by the minimum amount of waterneeded to dissolve all ether-insoluble material. The" layers wereseparated and the organic layer was washed with salt solution and driedover powdered magnesium sulfate. Evaporation to dryness afforded awhite, crystalline residue which was recrystallized from methylenedichloride-ether to give 1.5 g. of 17;3-methyl-5B-androstane-3a,12a,l7u-tri0l [1; R is CH R is H], M.P. 207-214 C. Thepurified sample was prepared by recrystallization from methylenedichloride-acetone, M.P. 210- 214 C., [011 +29.2 (1% in ethanol).

EXAMPLE 2 17,8 methyl-5B-androstane-3a,12a,17a-triol 3,12-diacetate [I;R is CH R is COCH was prepared from 17;?- methyl-58-androstane-3u,12u,17a-triol and acetic anhydride in pyridine, andrecrystallized from ether-pentane, M.P. 121-124 C., [ab +108.4.

Other esters can be prepared by replacing the acetic anhydride by otheracid anhydrides or acid halides, for example, propionic anhydride,caproyl chloride, dodecanoyl chloride, B-cyclohexylpropionyl chloride,benzoyl chloride, p-nitrobenzoyl chloride, phenylacetyl chloride,cinnamoyl chloride, p-chlorophenoxyacetyl chloride or nicotinoylchloride, which produce, respectively, the 3,12-dipropionate,3,12-dicaproate, 3,12-didodecanoate, 3,12-di- (fl-cyclohexylpropionate)3,12-dibenzoate, 3,12-di-(p-nitrobenzoate), 3,12-di-(phenylacetate)3,12-dicinnamate, 3,12-di-(p-chlorophenoxyacetate), or3,12-dinicotinoate of 17,3-methyl-5,6-androstane-3a,12a,17a-tri0l.

EXAMPLE 3 (a) l7amethyl-5,8androstane-3a,12a,17B-triol 12-acetate To16.0 g. (39.3 mmoles) of l7u-methyl-5fl-androstane-3a,12a,17fl-triol,3,12-diacetate in 650 ml. of methanol was added 32 ml. of 30% aqueouspotassium hydroxide and the resulting solution refluxed for 30 minutes.The reaction mixture was acidified with acetic acid (15 ml.) and thebulk of the methanol removed in vacuo at 45 C. Ether and methylenedichloride were added and the organic solution washed with saturatedsalt solution and dried over powdered magnesium sulfate, thenconcentrated to dryness. The residue was crystallized from ether toproduce 13.0 g. yield) of 17a-methyl-5B- androstane-3a,12a,17[3-triol12-acetate as a solvate, M.P. 118-122 C. (bubbling). A portion of thismaterial was further purified by chromatography on silica gel and thenrecrystallized from ethyl acetate to furnish a sample with M.P. 162.5163C., [aJ +74.4.

(b) 12a,17 3-dihydroxy-17a-methyl-5fl-androstan-3-one 12-acet ate [11; Ris a-CH Z is CH(a-OCOCH A solution of 9.50 g. (25.9 mmoles) of17u-methyl-5B- androstane-3a,12a,17fl-triol 12-acetate in ml. of acetonewas treated with 38 ml. of water and 10.5 g. of N- bromoacetamide. Theresulting solution was kept in the dark at 5 C. for 2 hours and thenpoured into 300 ml. of water containing 20 g. of sodium sulfite. Themixture was extracted with four portions of ether and the combinedextracts washed with water and saturated salt solution and dried overpowdered magnesium sulfate, then conc'entrated to dryness. The oilyresidue was crystallized from acetone-hexane, affording 4.85 g. of12a,17,8-dihydroxy 17oz methyl-5 8-androstan-3-one 12-acetate, M.P.127128.5 C. Concentration of the mother liquor afforded a second crop of2.0 g. of product (73% total yield), M.P. 121-129 C. Onerecrystallization of the first crop from acetone-hexane afforded asample with the melting point unchanged, [ab +82.5.

EXAMPLE 4 12a,17/8-dihydroxy-17u-methyl-5B-androstan-3-one [II; R isd-CH Z is CH(a-OH)] A mixture of 6.3 g. of12a,17/3-dihydroxy-17a-methyl- 5fi-androstan-3-one 12-acetate (Example3) and 15.0 g. of potassium hydroxide in 220 ml. of methanol wasrefluxed for four and one-half hours. The product was isolated andrecrystallized from acetone-hexane to give 3.0 g. of 12a,173-dihydroxy-17a-methyl-55-androstan-3-one, prisms, M.P. 174-176 C., [111+353".

EXAMPLE 5 12a,l7fl-dihydroxy-17a-methylandrost-4-en-3-one .12- acetate[III; R is lZ-CHa, Z is CH(a-OCOCH To a stirred solution of 4.46 g.(12.3 mmoles) of 120:,- 17B-dihydroxy-17a-methyl-5fl-androstan-3-one 12acetate (Example 3) in 45 ml. of acetic acid containing one drop ofhydrogen bromide in acetic acid was added dropwise a solution of 1.96 g.(12.3 mmoles) of bromine and 0.95 g. (11.6 mmoles) of fused sodiumacetate in 85 ml. of acetic acid. The reaction mixture was at oncepoured into water and the aqueous mixture extracted with two portions ofether. The ether extracts were combined and washed with 10% sodiumcarbonate and water and dried over powdered magnesium sulfate, thenconcentrated to dryness to give 5.1 g. of 4/3-bromo derivative as aclear colorless oil. Without further purification, this oil wasdissolved in 55 ml. of dimethylformamide and 3.36 g. of lithiumcarbonate and 3.82 g. of lithium bromide were added. The resultingsuspension was stirred magnetically and heated on a steam bath for 16hours. To the cooled reaction mixture were added 1 liter of ether and250 ml. of 1 N hydrochloric acid and the layers were separated. Theether layer was washed with saturated sodium bicarbonate solution,'waterand saturated salt solution and dried over powdered magnesium sulfate,then evaporated to dryness. Crystallization of the residue fromacetonehexane afforded 1.80 g. (40% yield) of12a,17fi-dihydroxy-17a-methyl-androst-4-en 3 one 12 acetate, M.P. l79183C. Two recrystallizations from the same solvent mixture gave a samplewith M.P. l86.5l88.5 C., [aJ +157.2, A 240 m (6 15,700).

EXAMPLE 6 12a,17fi-dihydroxy-17u-methylandrost-4en-3-one [III; R is a-cHZ is CH(oc-OH)] A solution of 1.00 g. (2.77 mmoles) of120;,17fi-dihydroxy-17m-methylandrost-4-en-3-one 12-acetate (Example 5)and 2.38 g. of potassium hydroxide in 35 ml. of methanol was refluxedfor 4.5 hours under nitrogen. The reaction mixture was acidified withacetic acid and the methanol was removed by concentration in vacuo at C.To the residue were added 300 ml. of ether and the minimum amount ofwater (10-20 ml.) necessary to dissolve the solid residue completely.The layers were separated and the ether layer was washed with saturatedsalt solution and dried over powdered magnesium sulfate and decolorizedwith charcoal, then concentrated to give apale yellow crystallineresidue. Recrystallization from acetone-hexane afforded 0.67 g. (76%yield) of 1211,1718- dihydroxy-l7ot-methylandrost-4-en-3-one, M.P.192-194 C. One recrystallization from the same solvent mixture furnisheda sample with M.P. 193l94.5 C., [a] +109.2; A 242 m (5 15,700).

EXAMPLE 7 A solution of 6.5 ml. of allyl bromide in ml. of absoluteether was added to 6.5 g. of magnesium turnings and the mixture allowedto stand until considerable cloudiness had developed (about 5 minutes).The liquid was removed by decanting and 125 ml. of anhydrous ether wasadded to the etched magnesium, thus prepared. To the vigorously stirredmixture was added dropwise in minutes a solution of 6.5 g. (21 mmoles)of 3a,l2ot-dihydroxy-Sfi-androstan-l7-one and 15.5 ml. (180 mmoles) ofallyl bromide in 40 ml. of tetrahydrofuran and 175 ml. of anhydrousether. Every 20 minutes during the dropwise addition, 2 g. portions ofmagnesium were added. At the end of the addition, the reaction mixturewas refluxed for 4 hours. More ether (150 ml.) and 250 ml. of methylenedichloride were added and the complex was decomposed by the addition of300 ml. of saturated ammonium chloride solution. The layers wereseparated and the organic layer was washed. with salt solution and driedover powdered magnesium sulfate, then concentrated to dryness.Recrystallization of the residue from acetone afforded 5.50 g. of17fl-allyl-5flandrostane-3a,12 z,17a-triol, M.P. 217219 C. Concentrationof the mother liquor gave 0.60 g. of material, M.P. 207214 C., which,upon recrystallization from acetone, furnished an additional 0.50 g.(total yield 81%), M.P. 216-218 C. A sample prepared byrecrystallization from acetone had the M.P. 219220 C. [0L];D+36.2.

By replacing the allyl bromide in the foregoing preparation by a molarequivalent amount of propargyl bromide, there can be obtainedl7fi-propargyl-5fi-androstane-3a, 12a,17a-triol [1; R is CHZCECH, R isH].

EXAMPLE 8 17fl-allyl-5B-androstane-3ac,l2a,l7a-triol 3,12-diacctate [I;R is CH CH CH R is COCH was prepared from17fi-allyl-5fl-androstane-3a,12a,17m-triol (Example 7) and aceticanhydride in pyridine, and had the M.P. 9798.5 C., [al l-1072".

EXAMPLE 9 17 3-propyl-5,8-androstane-3 a,12a,17a-triol [1; Ris CH CH CHR is H] To a solution of 10.0 g. (28.7 mmoles) of 175-allyl-5,B-ar1dr0Stane-3oc,l2a,l7ot-tli0l (Example 7) in 300 ml. of ethanol wasadded 1.0 g. of 10% palladium on carbon and the mixture was shaken atroom temperature with hydrogen at 55 p.s.i. Hydrogen uptake ceased afterone molar equivalent was absorbed (5 minutes). The catalyst was removedby filtration through filtercel, and the filtrate was concentrated todryness by warming in vacuo. Recrystallization of the residue fromacetone afforded 7.3 g. of 17,6-propyl-5B-androstane-Sa,120 17- triol,M.P. 205-207 C. A second crop of 1.8 g. (90% yield), M.P. 202205 C., wasobtained from the mother liquor. One recrystallization of the first cropmaterial from acetone afforded a sample with the melting pointunchanged, [a]; +18.3.

EXAMPLE l0 17fl-propyl-SB-androstane-3a,12m,17a-triol 3,12-diacetate [I;R is CH CI-I CH R' is OCOCH was prepared from 17 8 propyl-53-androstane-3m,12a,l7a-triol (Example 9) and acetic anhydride inpyridine. The product was recrystallized from methanol and had the M.P.l44l46 C., [OL]D+108.2.

EXAMPLE 1 1 17B-propyl-12a,l7a-dihydroxy-5/3-androstan-3-one [II; R is/8-CH CH CH Z is CH(ca-OH)] A solution of 6.6 g. (19 mmoles) of17fi-propyl-5flandrostane-3a,12a,17a-triol (Example 9) in ml. oft-butanol was treated with 5 ml. of pyridine, 5 -ml. of water and 3.2 g.(1.25 equiv.) of N-bromoacetamide, and the resulting solution kept for 7hours at room temperature. The reaction mixture was poured into 1.5liters of cold water containing 6 g. of sodium sulfite, and theprecipitate which formed was collected and dried and recrystallized frommethanol to give 3.0 g. (46% 'yield') of propyl-12a,17a-dihydroxy-53-androstan-3-one, M.P. 211-212 C. One recrystallization from methanolfurnished a sample with M.P. 215-216 C., [ot] +14.3, x 3.l0, 5.85

EXAMPLE 12 was prepared from 1713-propyl-12a,17a-dihydroxy-5B-androstan-S-one (Example 11) and acetic anhydride in pyridine, andpurified by recrystallization from acetonehexane. It had the M.P.126-128 EXAMPLE 13.

To the chromium trioxide-pyridine complex prepared by adding 5.8 g. ofchromium trioxide to 60 ml. of pyridine was added a solution of 2.9 g.(8.3 mmoles) of 1713- propyl-B-androstane-3a,12a,17u-triol (Example 9)in 20 ml. of pyridine and the resulting mixture stirred magnetically for20 hours at room temperature. The reaction mixture was diluted with hotbenzene and filtered through filterceland the filter cake rinsed withtwo portions of hot benzene. The combined filtrate was diluted withether and. washed successively with water, 2 N hydrochloric acid, 2Nsodium hydroxide, water and saturated salt solutionand dried overpowdered magnesium sulfate, then concentrated to dryness.Recrystallization of the residue fromacetone-hexane afiorded 1.8 g. (63%yield) of 175 propyl 17a; hydroxy-5,6-and rostane-3,12-dione, M.P.159160 C. One. recrystallization from the same solvent mixture gaveasample with M.P. 160-162 C [a] +46.1 (1% in acetone); i 2.85., 5.77,5.93 4.

EXAMPLE 14' l7 3-allyl-17a-hydroxy-5 8-androstane-3,12-dione To thechromium trioxide-pyridine complex prepared by adding 9 g. of chromiumtrioxide to 90 ml. of pyridine was added a' solution of 4.5 g. (13mmoles) of l7fiallyl- 5fi-androstane-3u,l2a,17a-triol (Example 7) in 30ml. of pyridine and the mixture stirredmagnetically at room temperaturefor 24 hours. The reaction mixture was diluted'with 350 ml. of hotbenzene, filtered through filtercel and the filter cake Washed with twoportions of hot benzene. The filtrate was diluted with ether and washedsuccessivelywith, water, '2 N'hydrochloric acid, water and saturatedsalt solution and dried over'powdered magnesium sulfate, decolorizedwith charcoaland then concenrated to a white crystalline residue.Recrystallization from acetone-hexane afforded 2.4 g. (54% yield) of17}?- allyl-17a-hydroxy-5B-androstane 3,12 dione, M.P. 156- 158 C. Asecond recrystallization from acetone-hexane produced a sample with themelting point unchanged, [oc] +31.s, k 2.84, 3 .28, 5.77, 5.93, 6.09,.

By the same procedure 17/3-propargyl-5/3-androstane 3a,12oc,17a-tli0lcan be oxided to l7B-propargyl-17ix-hydroxy-5i3-androstane-3,12-dione[II; R is FCH ECH; Z is C=O].

' EXAMPLE 15 12wHot-isopropylidenedioxy 17a methyl-SB-androstan- 311-[IV; R is CH R" and R are CH X is CH(oc-OH)] 1 A solution of 3.65 g.(11.3 mmoles) of l7fi-methyl-5 3- androstane-3oi,l2a,l7a-triol(Example 1) in 440 ml. of acetone containing 20 drops of 72%perchloricacid was kept for 3.5 hours at room temperature. The reactionmixture was treated with 220 ml. of water and then sufiicient saturatedsodium bicarbonate solution (about ml.) was addedto neutralize the acidpresent. The acetone was removed by concentration in vacuo at 50 C. andthe aqueous residue was extracted twice with ether. The ether extractswere combined and washed with saturated salt solution and dried overpowdered magnesium sulfate, then concentrated to dryness. The residuewas taken up in 1:9 methylene dichloride-ether and poured onto a columncontaining 120 g. of silica gel. The first 1000 ml.

of eluate aiforded crystalline material which was recrystallized fromether-pentane to give 1.8 g. (44% yield) of12a,17a-isopropylidenedioxy-l7fl-methyl-5 8-androstan- 3u-ol, M.P.l66169 C. Two recrystallization from the same solvent mixture afforded asample with M.P. 168.5 170 C., [a] +13.6.

By replacing the acetone in the foregoing preparation by a molarequivalent amount of methyl ethyl ketone, diethyl ketone or dibutylketone, there can be obtained, respectively,12a,17a-(2'-butylidenedioxy)-17fl-methyl-5B- androstan-3a-ol [IV; R isCH R" is C H R is CH X is CH(a-OH)], 12u,17u (3 pentylidenedioxy) 175-methyl-5fl-androstan-3a-ol [IV; R is CR R" and R are C H X is(CH(a-OH)], or 12oz,17ot-(5'-nonylidenedioxy)-17fl-methyl-5fl-androstan-3a-ol [IV; R is CH R" andR are C H X is CH(a-OH)].

In another run there was isolated from the chromatograph column abyproduct consisting of 17-methyl-5/3- androst-l6-ene-3a-12a-diol whichwas treated with acetic anyhdride in pyridine to give l7-methyl-58-androst-l6- ene-3a,l2u-diol 3,12-diacetate, M.P. 143-146 C. whenrecrystallized from methanol, [a] +110.9. The latter compound was foundto have myotrophic activity.

EXAMPLE 16 12oc,17a isopropylidenedioxy 17B-methyl-5B-androstan-3a-olS-acetate [IV; R is CH R" and R' are CH X is CH(aOCOCH was prepared from1.5 g. of 12a, 17a-isopropylidenedioxy-17,3-methyl-55-androstan 3oc-0land 7.5 ml. of acetic anhydride in 15 ml. of pyridine 16 hours at roomtemperature. The product was isolated and recrystallized fromacetonitrile to give 12a,17oc-iSOpi'0pylidenedioxy-17B-methyl-Sfi-androstan-3a ol 3 acetate, M.P. 122.5124.5C., [aJ +30.0.

EXAMPLE l7 12a,17a-isopropylidenedioxy 1713 methyl 5B androstan-3-one[IV; R is CH R" and R' are CH X is A solution of 0.15 g. (0.41 mmole) ofl2a,17a-isopropylidenedioxy-17fi-methyl-5fl-androstan-3a-ol (Example15), 0.17 g. (1.2 mmoles) of N-bromoacetamide, 1 ml. of pyridine, 1 ml.of water and 10 ml. of t-butyl alcohol was allowed to stand overnight atroom temperature in the dark and then poured into 25 ml. of watercontaining 0.25 g. of sodium sulfite. The aqueous mixture was extractedwith 4 portions of ether and the combined ether extracts were washedwith saturated salt solution and dried over powdered magesium sulfate,then concentrated to dryness. The residue was recrystallized fromether-pentane to give 92 mg. (62% yield) of12a,l7aisopropylidenedioxy-17 8-methyl-5fl-androstan-3-one, M.P. 164168C. A purified sample was prepared by recrystallization fromether-pentane, M.P. 162.5-165 C., [111 +13.1, x 5.86,.

EXAMPLE 18 12a,17a-isopropylidenedioxy-17fi-methylandrost-4-en- 3-one[V; R is CH R" and R are CH To a solution of 2.95 g. (8.2 mmoles) of12a,17a-isopropylidenedioxy-l7fi-methyl-5B-androstan-3-one (Example 17)in 60 ml. of dimethylformamide containing 0.03 g. of p-toluene-sulfonicacid was added in one portion a solution of 1.31 g. (8.2 mmoles) ofbromine in 15 ml. of dimethylformamide. The reaction mixture was keptfor 2.5 hours at room temperature, and during this period the solutiongradually lightened in color until it became almost colorless. It waspoured into ml. of saturated sodium bicarbonate solution in 750 ml. ofwater and the aqueous mixture extracted with two portions of ether. Theextracts were combined, washed with saturated salt solution and driedover powdered magnesium sulfate, then concentrated to dryness, affordingthe 4-bromo derivative as a white crystalline solid, M.P. -144 C. A 0.10g. portion of this solid was recrystallized twice from acetonitrile togive a small amount of material melting at 167-169 C., A 5 .79 u.

The bulk of the crude bromo ketone was dehyd-robrominated withoutfurther purification by dissolving it in 60 ml. of dimethylformamide,adding 3.0 g. of lithium carbonate and 3.2 g. of lithium bromide andheating the mixture for 18 hours on a steam bath with magnetic stirring.The reaction mixture was cooled and poured into water, then extractedwith two portions of ether. The extracts were combined and washed withwater and salt solution and dried over powdered magnesium sulfate, thenconcentrated to a small volume and cooled. The precipitate was collectedand dried to furnish 1.33 g. (45% yields) of12a,17a-isopropylidenedioxy-17 8-methylandrost-4-en-3- one, M.P. 200-207C. One recrystallization from methanol afforded a sample with M.P.207-210 C., [u] +524", x 241 mu (e 16,300).

12a,17a (2 butylidenedioxy)-17B-methyl-5fl-androstan-3a-ol;12a,17x-(3-pentylidenedioxy)-17/3-methyl-5[3- androstan-3a-ol; or12a,l7a-(5nonylidenedioxy)-17flmethyl-5B-androstan-3a-ol when subjectedto the procedures of Examples 17 and 18 can be converted, respectively,to 12a,l7a-(2-butylidenedioxy)-17B-methylandrost-4-en- 3-one [V; R is CHR" is C l-I R is CH 12a,17a- (3pentylidenedioxy)-17fl-methylandrost-4-en-3-one [V; R is CH R and R' areC H or l2a,17a-(5-nonylidenedioxy)-17fl-methylandrost-4-en-3-one [V; Ris CH R and R are C H EXAMPLE 1912a,l7a-dihydroxy-17-methylandrost-4-en-3-one [-III; R is B-CH Z isCH(a-OH)] A solution of 1.05 g. of 12a,17u-isopr0pylidenedioxy-17B-methylandrost-4-en-3-one in 30 ml. of acetic acid was treated with10 ml. of water, and the mixture was allowed to stand at roomtemperature for two and one-half hours. The mixture was diluted withwater and after an additional 30 minutes the solution was treated withsaturated sodium bicarbonate solution until alkaline and then extractedwith ether. The ether extracts were washed with water and sodiumchloride solution, dried and concentrated to dryness. The residue wasrecrystallized from acetone-hexane and from acetonitrile to give12a,17u-dihydroxy-17-methylandr0st4-en-3-one, M.P. 199.5-203 C., [a],+84.4.

EXAMPLE 20 175 allyl l2a,17a-isopropylidenedioxy-5B-androstan-3uolacetate [IV; R is CH CH=CH R" and R' are CH X is CH(a-OCOCH A suspensionof 4.3 g. (12 mmoles) of l7l3-allyl-5B- androstane-3a,12u,17u-triol(Example 7) in 430 ml. of acetone was stirred magnetically as 10 dropsof 70% perchloric acid was added. After the mixture had stirred for 10minutes, all material was in solution and an amber color had developed.The solution was kept for 3 hours at room temperature and then 200 ml.of water and 20 ml. of saturated sodium bicarbonate solution were added.The acetone was removed by warming in vacuo and the aqueous residue wasextracted with two portions of ether. The extracts were combined andWashed with saturated salt solution and dried over powdered magnesiumsulfate, then concentrated to dryness. The pale-yellow oily residue waspurified by chromatography on neutral alumina. Elution with 10%methylene dichloride-50% ether-40% pentane afforded 3.70 g. of175-allyl-12a,l7a-isopropylidenedioxy 5fl-androstan-3a-ol as an oilwhich resisted all attempts at crystallization; )t 3. 00, 3.31, 6.14,7.26, 731 The 3.70 g. of amorphous hydroxy compound was acetylated withacetic anhydride and pyridine and the product purified by chromatographyon neutral alumina. Elution with 10% ether-90% pentane affordedcrystalline material which was recrystallized from pentane to give 2.2g. of 17fl-allyl-12a,l7a-isopropylidenedioxy-Sfi-androstan-3ot- 01acetate, M.P. 134l37 C. A second recrystallization from pentanefurnished a sample with M.P. 136.5-l38 C., [cz] +ll.0, A 3.25, 5.74,6.11, 7.23, 7.30, 8.00

By replacing the 17p-allyl-5/3-androstane-3a,12a,17atriol in theforegoing preparation by a molar equivalent amount of17B-propargyl-SQ-androstane-3u,12a,l7a-triol there can be obtained 17flpropargyl-12a,l7a-isopropylidenedioxy-5B-androstan-3a-ol and its acetate[IV; R is CHZCECH, R" and R" are CH X is CH (a-OCOCH EXAMPLE 21l7fi-propyll2a,17a-isopropylidenedioxy 5p androstan- 3a-ol acetate [IV;R is CH CH CH R" and R'" are CH X is CH(a-OCOCH To a solution of 1.1 g.(2.6 mmoles) of 17 3-allyl-12a, 17a-isopropylidenedioxy-SB-androstan-3a-ol acetate (Example 20) in 300 ml. of ethanol was added0.5 g. of 10% palladium on carbon and the resulting mixture shaken in 1atmosphere of hydrogen until one molar equivalent was absorbed (2.5minutes). The catalyst was removed by filtration through filtercel andthe filtrate concentrated by warming in vacuo. The residue was taken upin ether and dried over powdered magnesium sulfate and concentrated todryness. The residue was recrystallized from methanol to give 0.84 g.(76% yield) of 17fl-propyl-12a, l7a-isopropylidenedioxy 5t? androstan-3a-0l acetate, M.P. 116118 C. One recrystallization from methanolafforded a sample with the melting point unchanged, [a] +26.1.

EXAMPLE 22 (a) l7a-hydroperoxy-3a,12a-dihydroxy-5/3-pregnan-ZO- oneOxygen gas was bubbled through a solution of 30.0 g. of potassiumt-butoxide in 200 ml, of dry t-butanol (dried by distillation fromcalcium hydride) for 5 minutes at room temperature and then a solutionof 6.0 g; (18 mmoles) of 3a,1Za-dihydroxy-Sfl-pregnan-ZO-one in 60 ml.of dry t-butanol was added in one portion. Oxygen was bubbled throughthe resulting solution for 60 minutes and the reaction mixture was atonce poured into 3 liters of water containing 60 ml. of acetic acid. Theprecipitate which formed was collected and dried to give 4.0 g. of'l7a-hydroperoxy-3a,12a-dihydroxy 5 3 pregnan-ZO-one, M.P. l42144 C.(dec.). Two recrystallizations from methanol afforded 1.0 g. ofmaterial, M.P. 152" C. (dec.), [u] +63.6 (1% in MeOH), A 2.80, 2.93,3.16, 5.88, 1153a.

(b) 3a,12a,17a-trihydroxy-5fl-pregnan-ZO-one To a solution of 0.'l8 g.(0.49 mmole) of 17a-hydroperoxy-3a,l2a-dihydroxy-5b-pregnan-ZO-one in 50ml. of acetic acid was added 0.60 g. of acid-washed zinc dust and themixture stirred for 4.5 hours at room temperature. The mixture wasfiltered, the zinc washed with methylene dichloride, and the filtrateconcentrated to a small volume by warming in vacuum. The residue wasdissolved in methylene dichloride and washed successively with saturatedsodium bicarbonate solution, water and saturated salt solution and driedover powdered magnesium sulfate, then concentrated to dryness. Theresidue was recrystallized twice from acetone-hexane to give 75 mg. of3a,12a,-17a-trihydroxy-S/B-pregnan-ZO-one, M.P. 192 C., [a] +77.1.

(c) 3a-hydroxy-l2a,17a-isopropylidenedioxy-Sfl-pregnan- 20one [VI; R"and R" are CH X is CH(oc-OH)] A solution of 1.76 g. (5.0 mmoles) of3a,12a,17a-t1'ihydroxy-SB-pregnan-ZO-one in 200 ml. of acetonecontaining 7 drops of 70% perchloric acid was kept at room temperaturefor 4 hours and then 100 ml. of water and 7 ml. of saturated sodiumbicarbonate solution were added. The acetone was removed by warming invacuum and the aqueous residue extracted with two portions of ether. Theorganic extracts were combined and washed with saturated salt solutionand dried over powdered magnesium sulfate, then concentrated to dryness.The oily residue was chromatographed on 60 g. of silica gel and thematerial eluted with 10% methylene dichloride-50% ether-40% pentane wasrecrystallized from ether-pentane to,give 0.92 g. (47% yield) of3a-hydroxy-12a,17a-isopropylidenedioxy-SB-pregnan-ZO-one, M.P. 174176C.,

[M +129", A 2.84, 5.87;t.

. By replacing the acetone in the foregoing preparation by a molarequivalent amount of methyl ethyl ketone or dibutyl ketone there can beobtained, respectively, 30:-hydroxy-12a,17a-(2-butylidenedioxy)-5,B-pregnan-20-one [VI; R" is CH R'is C H X is CH(a-OH)] or Bot-hydroxy-1-2a,l7a-(5'-nonylidenedioxy) 5,3pregnan-ZO-one [VI; R" and R are C H X is CH(u-OH)].

' EXAMPLE 23 (a) 12m,17a-dihydroxy-5fi-pregnane-3,20-dione *Oxidation of305,1211,17a-trihydroxy-5fi-pregnan-20-one with'N-bromoacetamide intertiary-butanol solution containing traces of pyridine and water,atforded 12a,17udihydroxy-Sfl-pregnane-3,20-dione in 61% yield, M.P.210-21'1 C.

(b) 12a;17a-isopropylidenedioxy-SB-pregnane-3,20-dione [VI; R" and R"are CH X is C=O] A solution of 4.0 g. (11.5 mmoles) of12a,17a-dihydroxy-Sfl-pregnane-S,20-dione in 400 m1. of acetonecontaining 40 drops of 70% perchloric acid was kept at room temperaturefor three hours. Water (200 ml.) and 50 ml. of saturated sodiumbicarbonate solution were added and the acetone was removed by warmingin vacuum. The aqueous residue was extracted with ether and the organicextract washed with salt solution and dried over powdered magnesiumsulfate, then concentrated to dryness. The clear, oily residue wasdissolved in 50 ml. of ether and 450 ml. of pentane was added. Aprecipitate formed which was collected and recrystallized from ethylacetate to give 0.67 g. of 12a,l7a-dihydroxy-5B-pregnane-3,20- dione,M.P. 204-209 C. The ether-pentane filtrate was poured onto a columncontaining 150 g. of silica gel and the column eluted with a 1:4ether-pentane mixture. The product thus eluted from the column wasrecrystallized from pentane to give 1.44 g. (39% yield) of12:1,17oc-iS0- propylidenedioxy 5 3 pregnane 3,20 dione, M.P. 135-136.5" C., [ab +15.0, A 5.82

EXAMPLE 24 3u-hydroxy-12a-isopropoxy-5fl-androstan-17-one[VII; R" and Rare CH Z is C=O, X is CH(a-OH)] A suspension of 9.7 g. (31.3 mmoles) ofSfI-androstane- 13a,12a,17fi-triol in 600 ml. of acetone was treatedwith 12 ml. of boron trifluoride etherate, and the solid dissolved inabout ten minutes. The solution was kept for 2 hours at room temperatureand then poured into 300 ml. of saturated sodium bicarbonate dilutedwith 300 ml. of water. The acetone was removed by warming in vacuum andthe aqueous residue extracted with 600 m1. of ether. The layers wereseparated and the organic layer washed with water and saturated saltsolution and dried over powdered magnesium sulfate, then concentrated todryness. Recrystallization of the residue from ether-pentane gave 5.85g. of 3a-hydroxy-12a-isopropoxy-5j3-androstan- '17-one, M.P. 138- 148 C.Two further recrystallizations from ether-pentane atforded 3.5 g. ofmaterial which melted at 148150 C. Recrystallization from acetonitrilegave'a sample with M.P. 150.5152 C., [ab +172.0, A 2.86, 576 NMR twot-CH 1. 28 and 1.43 p.p.m.; two sec-0H 1.58 and 1.62 ppm. (J=7 c.p.s.).

By replacing the acetone in the foregoing preparation by a molarequivalent amount of ethyl methyl ketone or dibutyl ketone, there can beobtained, respectively, 30:-

EXAMPLE 25 l2a-isopropoxy-5B-androstane-3a,17fl-diol [VII; R" and R areCH Z is CH(/3-OH), X is CH(a-QH)] To a stirred suspension of 3.0 g. oflithium aluminum hydride in 300 ml. of 'tetrahydrofuran was addeddropwise a solution of 3.0 g. (8.6 mmoles) of 3a-hydroxy-12a-isopropoxy-Sflandrostaml7-one (Example 24) in 300 ml. of tetrahydrofuranand the mixture heated under reflux for 18 hours. The excess hydride wasdecomposed 'by careful addition of 6 ml. of water, the mixture filteredthrough Celite and the precipitate washed with tetrahydrofuran. Thefiltrate was concentrated to dryness and the residue crystallized fromether-pentane to furnish 2.2 g. (73% yield) of12a-isopropoxy-Sfi-androstane-Ba,17fi-diol, M.P. l77l78 C. One furtherrecrystallization from etherpentane afforded a sample with M.P. 178180C., [a] +78.7.

EXAMPLE 26 12a-isopropoxy-SB-androstane-3,17-dione [VII; R" and R" areCH Z and X are C=O] A solution of 36.0 g. (0.103 mole) of3a-hydroxy-12uisopropoxy5B-androstan-17-one (Example 24) in 600 ml. oft-butanol containing 25 ml. of water, 25 ml. of pyridine and 17.8 g.(1.20 equiv.) of N-bromoacet-amide was kept overnight at roomtemperature in the dark and then poured into 4 liters of cold watercontaining 36 g. of sodium sulfite. The aqueous mixture was extractedwith three l-liter portions of methylene dichloride and the combinedextracts washed with dilute hydrochloric acid, dilute sodium hydroxide,water and saturated salt solution and dried over powdered magnesiumsulfate, then concentrated to dryness. Crystallization of the residuefrom methylene dichl-oride-ether-pentane afforded 16.3 g. ofl2a-isopropxy- 5fi-androstane-3,17-dione, M.P. 112.5 C. A 3.0 g. portionwas recrystallized once from ether-pentane to give 2.1 of pure material,M.P. 113ll5 'C., [ab +163.5. An additional 11.7 g. (77% total yield) ofproduct, MJP. 113-116" C., was obtained by saturation of the aboveaqueous layer with ammonium sulfate, re-extraction with methylenedichloride, combination of this extracted material with that from thetwo recrystallization mother liquors and purification by chromatographyon silica gel.

EXAMPLE 27 12ot-isopropoxyandrost-4-ene-3,17-dione [VIII; R" and R' areCH Z' is C=O] To a stirred solution of 25.5 g. (73.5 mmoles) of12aisopropoxy-Sfi-androstane-3,17-dione (Example 26) in ml. of aceticacid containing one drop of 30% hydrogen bromide in acetic acid wasadded dropwise 11.75 g. (1 equiv.) of bromine in 150 ml. of acetic acid.The reaction mixture was at once poured int-o 2 liters of water and thebulk of the acid neutralized by adding about 1.5 liter of 10% sodiumcarbonate solution. Ether was added, the layers separated, and theorganic layer washed with water, saturated sodium bicarbonate solutionand saturated salt solution and dried over powdered magnesium sulfate,then concentrated to dryness. The brown, viscous, oily 4flbromoderivative (34 g.), thus obtained, was used without furtherpurification. The oil was dissolved in 250 ml. of dimethylformamide andstirred with 22 g. of lithium carbonate and 25 g. of lithium bromide for18 hours with heating on a steam bath. Ether and water were added andthe layers were separated. The ether layer was washed with water andsaturated salt solution and dried over powdered magnesium sulfate, thenconcentrated to dryness. The residue was recrystallized twice frommethanol to furnish 11.0 g. (43% yield) of 12a-isopropoxyandrost-4-ene-3,l7-dione, M.P. 16l-162 C. One further recrystallization from thesame solvent afforded a sample with M.P. 162-164 c., 0. +222.1; x 240 mp(e 16,200).

EXAMPLE 28 17B-hydroxy-12u-isopropoxyandrost-4-en-3-one [VIII; R" and R'are CH Z is CH(fi-OH)] To a stirred suspension of 3.45 g. of lithiumaluminum hydride in 300 ml. of tetrahydrofuran was added dropwise asolution of 3.45 g. (10.0 mmoles) of12x-isopropoxyandrost-4-ene-3,17-dione (Example 27) in 300 ml. oftetrahydrofuran and the mixture heated under reflux for 18 hours. Water(7 ml.) was added cautiously and the precipitate removed by filtrationthrough Celite and washed with tetrahydrofuran. The combined filtrateand washings were concentrated to dryness to furnish a white,crystalline residue which was dissolved in 50 ml. of dioxane and treatedwith 3.0 g. (13 mmoles) of 2,3-dichloro-5,6-dicyanoquinone. Theresulting solution was stirred for three hours at room temperature andthe precipitate which formed during that time was collected and washedwith dioxane. The filtrate and washings were combined and concentratedin vacuum at 50 C. and the residue dissolved in methylene dichloride andwashed with 2 N sodium hydroxide and water and dried over powderedmagnesium sulfate, then concentrated to dryness. The red, oily residuewas crystallized from ether-pentane to produce 2.2 g. of material, M.P.94-99 C. Two further recrystallizations from the same solvent mixtureafforded 1.57 g. (45% yield) of17;8-hydroxy-l2a-isopropoxyandrost-4-en-3-one, M.P. 9396 C., [11]+125.8; x 243 m (6 14,800); k 3.00 (OH at C-17), 5.96 (conjugated CO atC-3), 6.19 (C=C).

17B-hydroxy-12a-isopropoxyandrost-4-en-3-one can be oxidized withaluminum isopropoxide and acetone in benzene solution, heating for abouttwelve hours, to give 12aisopropoxyandrost-4-ene-3,17-dione.

EXAMPLE 29 (a) 12a,17fl-dihydroxyandrost-4-en-3-one 17-trifiuoroacetate[X; R" is COCF Z is CH(a-OH)] A solution of 8.0 g. (23.2 mmoles) ofl2a-isopropoxyandrost-4-ene-3,l7-dione (Example 27) in 50 ml. oftrifluoroacetic acid was kept for 22 hours at room temperature and thenpoured into 250 ml. of 10% sodium carbonate solution. Additional sodiumcarbonate solution was added until the mixture was alkaline, ether wasadded and the layers were separated. The ether layer was washed withsaturated salt solution and dried over powdered magnesium sulfate, thenconcentrated to dryness. The sticky crystalline residue wasrecrystallized twice from methylene dichloride-ether to furnish 2.50 g.of 12:1,17 3- dihydroxyandrost-4-en 3 one 17-trifiuoroacetate, M.P.2l3-216 C. Recrystallization from acetonitrile gave a sample with M.P.218-2l9 C., [oc] +589"; x 241 mg (a 16,500); m 2.94 (OH at C-l2), 5.60(OCOCF at C-17), 6.01a (conjugated CO at C-3).

(b) 12a,17fl-dihydroxyandrost-4-en-3-one [X; R" is H, Z is CH(oc-OH)]All mother liquors from part (a) were combined and concentrated todryness to give 7.5 g. of an oil which was dissolved in 500 ml. ofmethanol, treated with 10 g. of potassium hydroxide in 25 ml. of waterand heated under reflux for minutes. The solvents were removed bywarming in vacuum and the residue partitioned between 500 ml. ofmethylene dichloride and 60 ml. of water. The organic layer wasseparated and washed with water and saturated salt solution and driedover powdered magnesium sulfate and concentrated to give 5.2 g. of abrown oil which was chromatographed on silica gel. Elution with 1:9methylene dichloride-ether afforded 0.65 g. of residue which wasrecrystallized from methanol to furnish 0.40

g. of 12a-isopropoxyandrost-4-ene-3,l7-dione, M.P. 159 163" C. Elutionwith 1:9 methanol-ether afiorded, after two recrystallizations fromethyl acetate, 2.03 g. of 12a,17p-dihydroxyandrost-4-en-3-one, M.P.148-150" C. One further recrystallization from the same solventfurnished a sample with M.P. l50-l52 C., [a] +l29.l; x 241 m (e 16,300);k 2.94 (OH at C-12 and C-17), 6.04 (conjugated CO at O-3), 621a (C=C).

12a,17fl-dihydroxyandrost-4-en-3-one can be esterified withtriiiuoroacetic acid at room temperature to give thel7-trifluoroacetate.

12a,17/3-dihydroxyandrost-4'en-3-one can be oxidized with chromic oxidein acetic acid to give 4-androstene-' 3,12,17-trione.

EMMPLE 30 12a,17fi-dihydroxyandrost-4-en-3-one diacetate [X; R is COCH Zis CH(a-OCOCH (A) From 12a,17fl-dihydroxyandrost-4-en-3-one.A 0.90 g.sample of 12a,17fi-dihydroxyandrost-4-en-3-one (Example 29) wasacetylated with acetic anhydride and pyridine and the productrecrystallized from ether-pentane to give 0.67 g. of12a,17fl-dihydroxyandrost-4-en-3-one diacetate, M.P. 192-195 C., andundepressed upon admixture with a sample, M.P. l91194 C., preparedbelow; the infrared spectra of the two samples were identical.

(B) From 12a-hydroxyandrost-4-ene-3,l7-dione.-A solution of 1.70 g.(5.62 mmoles) of l2a-hydroxyandrost- 4-ene-3,17-dione in ml. oftetrahydrofuran was added dropwise to a stirred suspension of 1.70 g. oflithium aluminum hydride in 175 ml. of tetrahydrofuran and the mixtureheated under reflux for 5 hours. Water (3.5 ml.) was added dropwise, theinsoluble material removed by filtration through Celite and the filtrateconcentrated to dryness. The viscous, oily residue was dissolved in 25ml. of dioxan, treated with 1.65 g. (7.3 mmoles) of 2,3-dichloro-5,6-dicyanoquinone and stirred for 2 hours at room temperature.The precipitate which had formed was removed by filtration and washedwith several portions of dioxan and the combined filtrate and washingsconcentrated to dryness. The residue was dissolved in methylenedichloride and washed with 2 N sodium hydroxide and water and dried overpowdered magnesium sulfate, then evaporated to dryness and the oilyresidue chromatographed on silica gel. Elution with 5% methanol in etheraflorded 0.93 g. of oil which was shown by thin layer chromatography(1:9 methanol-ether) to be mainly 12a,17B-dihydroxyandrost-4-en-3-one,but which could not be induced to crystallize from ethyl acetate.Acetylation of the crude oil with acetic anhydride and pyridine andpurification of the product by recrystallization from methylenedichloride-ether-pentane gave 0.60 g. of12a,l7fl-dihydroxyandrost-4-en-3-one diacetate, M.P. 19l- 194 C.Recrystallization from acetonehexane gave a sample with M.P. 194196 C.;[04] +130.2 A 240 my. (6 17,300); a 5.73, 5.77 and 7.92 (OCOCH at C-12and C-17, 6.00 (conjugated CO at C-3), 6.19 3 (C=C).

12a,l7fl-dihydroxyandrost-4-en-3-one diacetate can be saponified withpotassium hydroxide in methanol solution to give12a,17/3-dihydroxyandrost-4-en-3-one (Example 29).

EXAMPLE 31 l7fi-hydroxyandrost-4-ene-3,12-dione trifiuoroacetate [X;R"is COCH Z is C=O] A solution of 1.33 g. (3.3 mmoles) ofl2a,l7/3-dihydroxyandrost-4-en-3-one 17-trifluoroacetate (Example 29) in8 ml. of pyridine was added to 2.36 g. of chromium trioxide in 25 ml. ofpyridine. The mixture was kept overnight at room temperature, dilutedwith hot benzene, filtered through Celite and the filter cake rinsedwith two portions of hot benzene. The filtrate and washes were combined,diluted with ether and washed with water, 2 N

17 hydrochloric acid, ZN sodium hydroxide, water and saturated saltsolution and dried overpowdered magnesium sulfate, then concentrated todryness to give about 0.5 g. of white, crystalline residue. The aqueouswashes were re-extracted with methylene dichloride to furnish anadditional 0.33 g. of crystalline material. Chromatography of the totalproduct on silica gel and elution with methylene.dichloride-% ether-55%pentane afforded (afterrekiiystalliz'ation from acetonehexane) 0.25 g.of 17fi-hydroxyandrost-4-ene-3,12-dione trifiuoroacetate, M.P. 216 218,.C [oc] +141.0; A 238 m (12 16,700); )x 5.65 (OCOCF at C-17), 5.88 (CO atC-12), 5.96 (conjugated CO at O3), 6.19 (C=C).

can be hydrolyzed with potassium hydroxide in methanol to, give17fl-hydroxy-4-and1'ostene-3,12-dione, which in turn can be oxidizedwith chromic' oxide in acetic acid to give 4-androstene-3,12,17-trione.

Iclaim: 1 A compound arrherormn wherein R is lower-alkyl, lower alkenylor loweralkynyl; and R' is hydrogen or carboxylic acyl having up totwelve carbon atoms.

2. 17p lower-alkyl-5,8-androstane 3u,12a,17a-tri0l or a3,12-di-1ower-carb0xylic acid ester thereof.

3. 17,63-a1lyl-5 3-androstane 3u,12a17a-triol or a 3,12-di-lower-carboxylie acid ester thereof.

4. A compound of the formula wherein R is lower-alkyl, lower-alkenyl orlower-alkynyl; and Z is CH(a-OH), CH(a-OAcyl) or C=O, Acyl beingcarboxylic acyl having up to twelve carbon atoms.

5. 17-1ower-alkyl-l2a,17 dihydroxy 5fl-androstan-3- one.

6. l7-lower-alkyl l2a,l7-dihydroxy 4-androsten -3- one.

7. A compound of the formula wherein X is CH(a-OH), CH(u-OACY1) or C=O,Acyl being carboxylic acyl having up to twelve carbon atoms; R islower-alkyl, lower-alkenyl or lower-alkynyl; and R" and R arelower-alkyl.

8. 175-lower alkyl 1211,17-isopropylidenedioxy 5fiandrostan-3a-ol or a3-lower-carboxylic acid ester thereof. V

9. 12a,17a-isopropylidenedioxyl-17p methylandrost- 4 510. A compound ofthe formula v wherein X is CH(a-OH), CH(a-OAcyl) or C=O; Z is CH(/3-OH),CH (B-OAcyl) or C=O; and R" and R'" are lower-alkyl; Acyl in eachinstance being carboxylic acyl having up to twelve carbon atoms.

14. The process for preparing a compound of the formula Bill 9 wherein Rand R' are lower-alkyl, which comprises reacting5fl-androstane-3a,l2a,17}8 triol with a ketone, RCOR", in the presenceof a strong acid catalyst.

15. A compound of the'formula wherein R"" is hydrogen or carboxylic acylhaving up to twelve carbon atoms; and Z is CH(a-OH), CH(a-OAcyl) or C=O,Acyl being carboxylic acyl having up to twelve carbon atoms.

is trifiuoroacetyL 3,405,127 419 20 16. A compound according to claim 15wherein R"" androsten-12a-ol-3-0ne which comprises treating with tri-.fluoroacetic acid a compound of the formula 17.12a,175-dihydroxy-4-andr0sten-3-one. R a

18. 12a,17B-diacetoxy-4-androsten-3-0ne. i

19. The process for preparing 4-androstene-12a,17fi- 5 R di0l-3-onewhich comprises treating with a strong acid a compound ofthe formulawherein R" and R. are lower-alkyl! -15 References Cited I UNITED STATESPATENTS' 3,141,017 7/1964 Diassi 260239.55 3,030,391 4/1962 Diassi260-397.45

OTHER REFERENCES Meystre and Wettstein, Helv. Chim. Acta 32, pp. 1978-1992 (Chem. Abstracts,yol. 45, p. 4256d).

wherein and m are lower alkyl 25 LEWIS GOTTS,,Priinary Examiner.

20. The process for preparing 17fi-trifiuoroacetoxy-4- E. G. LOVE,Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,405,127 October 8, 1968 Philip E. Shaw It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below:

Column 1, line 44, below the formula insert I Colun 3, line 13, belowthe right-hand formula insert V line 45 "is tertiary-" should read intertiaryline 50, "l7a" should read l7a- Column 9, line 55, "B=CH ECH"should re B-CHZCECH Column 10, line 13, "3a should read 3o same line 13,CR should read CH Column 12, line 54, "5b" should read 56- Column 13line 55 "13a ,1201, 178- should read 3a,l2a,l76 Column l4, line 42,"2.1" should read 2.1 g. line 75, "12a" should read lZa- Column 18, line4, "-isopropylidenedioxyl-" should read -isopropylidenedioxy line 22,"hdroperoxy should read hydroperoxy- Signed and sealed this 24th day ofFebruary 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. I WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

